Bacterial communities track changes in their population densities by producing, releasing, and detecting diffusible signalling molecules called autoinducers. This process is called quorum sensing, as described in Miller, M. B. and Bassler, B. L. Quorum sensing in bacteria. Annu. Rev. Microbiol. 55, 165-199 (2001) and Waters, C. M. and Bassler, B. L. Quorum sensing: cell-to-cell communication in bacteria. Annu. Rev. Cell Dev. Biol. 21, 319-346 (2005), both of which are hereby incorporated by reference into this application. Population-wide responses of the bacteria to the accumulation of autoinducers shape group behaviors such as biofilm formation, virulence factor expression, bioluminescence, and sporulation, as described in Davies, D. G. et al. The involvement of cell-to-cell signals in the development of a bacterial biofilm. Science 280, 295-298 (1998); Passador, L., Cook, J. M., Gambello, M. J., Rust, L., and Iglewski, B. H. Expression of Pseudomonas aeruginosa virulence genes requires cell-to-cell communication. Science 260, 1127-1130 (1993); Eberhard, A. et al. Structural identification of autoinducer of Photobacterium fischeri luciferase. Biochemistry 20, 2444-2449 (1981); and Solomon, J. M., Lazazzera, B. A., and Grossman, A. D. Purification and characterization of an extracellular peptide factor that affects two different developmental pathways in Bacillus subtilis. Genes Dev. 10, 2014-2024 (1996), all of which are hereby incorporated by reference into this application. Vibrio cholerae bacteria use two parallel quorum-sensing systems (FIG. 1) to assess population density, as described in Miller, M. B., Skorupski, K., Lenz, D. H., Taylor, R. K., and Bassler, B. L. Parallel quorum sensing systems converge to regulate virulence in Vibrio cholerae. Cell 110, 303-314 (2002), both of which are hereby incorporated by reference into this application. In one system, the CqsS receptor responds to a molecule called Cholerae Autoinducer-1 (CAI-1), which is produced by the enzyme CqsA. CqsS is the Cholerae quorum-sensing Sensor and CqsA is the Cholerae quorum-sensing Autoinducer-synthase enzyme. In the second system, the LuxPQ receptor complex responds to the autoinducer-2 (AI-2) molecule, made by the LuxS enzyme. These two autoinducers, CAI-1 and AI-2, function synergistically to control gene regulation. CAI-1 is produced by several Vibrio species, suggesting that it functions as an intra-genus signal whereas AI-2 is produced and detected by a wide variety of bacteria and is presumed to facilitate interspecies communication, as described in Henke, J. M. and Bassler, B. L. Three parallel quorum-sensing systems regulate gene expression in Vibrio harveyi. J. Bacteriol. 186, 6902-6914 (2004), and Xavier, K. B. and Bassler, B. L. LuxS quorum sensing: more than just a numbers game. Curr. Opin. Microbiol. 6, 191-197 (2003), both of which are hereby incorporated by reference into this application. AI-2 is a set of interconverting molecules all derived from the precursor (S)-4,5-dihydroxypentane-2,3-dione (DPD), as described in Schauder, S., Shokat, K., Surette, M. G., and Bassler, B. L. The LuxS family of bacterial autoinducers: biosynthesis of a novel quorum-sensing signal molecule. Mol. Microbiol. 41, 463-476 (2001) and Miller, S. T. et al. Salmonella typhimurium recognizes a chemically distinct form of the bacterial quorum-sensing signal AI-2. Mol. Cell. 15, 677-687 (2004), both of which are hereby incorporated by reference into this application. In the Vibrios, the active AI-2 moiety is the furanosylborate diester (2S,4S)-2-methyl-2,3,3,4-tetrahydroxytetrahydrofuran borate. CAI-1 has a much more dramatic influence on target gene expression than AI-2, and is therefore the major quorum-sensing signal in V. cholerae, as described in Miller et al. (2002).
The prevalence of cholera disease in developing nations and the rise of antibiotic resistant strains of V. cholerae is a recognized health problem, as described in Wang, L. H. et al. A bacterial cell-cell communication signal with cross-kingdom structural analogueues. Mol. Microbiol. 51, 903-912 (2004), hereby incorporated by reference into this application. On a broader scale, a wide spectrum of bacterial diseases are known which require new therapeutic strategies as bacteria develop antibiotic resistance. It would be beneficial if, rather than searching for new antibiotics, a new therapeutic strategy were to be formulated for these bacterial diseases. On a still broader scale, bacterial pathogens infect animals and there is a need to control these animal diseases. For example, Vibrio harveyi and closely related species are pathogens of shrimp, molluscs and fish. There is a strong need to develop compounds and strategies to control pathogens of food animals such as those in the aquaculture industry. Thus, on the broad scale, there is a need to develop strategies to manipulate quorum-sensing-controlled processes in bacteria.